Bis-quaternary pyridinium salts

ABSTRACT

(2-HYDROXYIMINOMETHYLPYRIDINIUM - 1 - METHYL) - (RPYRIDINIUM-1-METHYL) ETHERS, WHEREIN R IS EITHER HYDROGEN, METHYL, METHOXYCARBONYL, ALDOXIMINE OR AMINOCARBONYL, ARE USEFUL AS PHARMACEUTICALS FOR TREATING AND ALLEVIATING SYMPTOMS OF POISONING CAUSED BY PHOSPHORUS-CONTAINING PLANT-PROTECTIVE AGENTS AND WAR GASSES.

nited States Patent 3,773,775 BIS-QUATERNARY PYRIDINIUM SALTS Ilse Hagedorn, Darmstadt, Germany, assignor to Merck Patent Gesellschaft mit beschrankter Haftung, Darmstadt, Germany No Drawing. Filed Aug. 27, 1968, Ser. No. 755,752 Int. Cl. C07d 31/40 U.S. Cl. 260-2955 A 3 Claims ABSTRACT OF THE DISCLOSURE (2 hydroxyiminomethylpyridinium 1 methyl) (R- pyridinium-l-methyl) ethers, wherein R is either hydrogen, methyl, methoxycarbonyl, aldoxime or aminocarbonyl, are useful as pharmaceuticals for treating and alleviating symptoms of poisoning caused by phosphorus-containing plant-protective agents and war gases.

SUNMARY OF THE INVENTION Quaternary ammonium pyridinium salts of the formula wherein R is either --H, CH COOCH -CH=NOH or -C0NH and is in any one of the positions 2-, 3- and 4-; and X is an equivalent of a monoor polyvalent anion; counteract the symptoms of poisoning caused by modern phosphorus-containing plant-protective agents and war toxicants. Those compounds wherein the anion is such that the quaternary salts I are not pharmaceutically acceptable may be converted by well-established procedures into therapeutically useful quaternary salts I. The therapeutically useful salts are independent of the position of R or its particular meaning within the indicated group; they can be administered orally, parenterally or topically to mammals poisoned by a phosphorus-containing compound of the type noted. The daily dosage varies from compound to compound and is dependent upon the severity of the poisoning being treated. Suitable doses are from 50 milligrams (mg) to 20 grams (g.) and can be administered as a single dose.

Compounds I are prepared, e.g. by reacting a compound of one of the formulas:

S N: -CH;-OCH;Y

(111) wherein R and X have their above-noted meanings; and Y is a residue which can be substituted by a compound of Formula IV;

with a corresponding compound of the formula:

3,773,775: Patented Nov. 20, 1973 p ce Another object is to provide intermediates II and III for the preparation of compounds I.

A still further object is to provide a pharmaceutical preparation containing an effective dosage of a compound of Formula I in addition to conventional carriers and additives, particularly wherein the compound of Formula I is [(Z-hydrOXy-iminomethyl)-pyridinium-(1)- methyl]-[(3-carbamoyl)-pyridinium-(1)-methyl] ether dichloride. It is also an object of the present invention to provide a pharmaceutical preparation containing an effective dosage, e.g. 50 mg. to 20 g. of [(Z-hydroxyiminomethyl) pyridinium (l)-methyl]-[(4-hydroxyiminomethyl) pyridinium (1)-methyl]-ether dichloride in addition to conventional carriers and additives.

Still further objects are apparent from the description and examples which follow.

DETAILED DISCUSSION OF THE INVENTION Of the quaternary pyridinium salts of Formula I, preferred embodiments are:

bis- Z-hydroxy-iminomethyl) -pyridinium-( 1 )-methyl] ether dichloride;

[ (Z-hydroxy-iminomethyl) -pyridinium- 1 )-methyl] (3- hydroxy-iminomethyl) -pyridim'um- 1 )-methyl] -ether dichloride;

[ (Z-hydroxy-iminomethyl) -pyridinium-( 1 )-methyl] [4- hydroxy-iminomethyl) -pyridinium-( 1 -methyl] -ether dichloride;

[ (2-hydroxy-iminomethyl) -pyridinium- 1 )-\methyl] (3 cagaamoyl) -pyridinium- 1 -methyl] -ether dichloride; an

[ Z-hydroxy-iminomethyl -pyridinium- 1 -methyl] [pyridinium- 1 )-methyl] -ether dichloride.

In the preparation of compounds I, any compound II is reacted with any compound IV, or any compound III is reacted with pyridine-2-aldoxime. In compounds II and III substituent Y is preferably a halogen, e.g. chloro and bromo, or R -SO O, such as alkylsulfonyloxy, particularly lower alkylsulfonyloxy having from 1-4 carbon atoms, e.g. methylsulfonyloxy, or arylsulfonyloxy, preferably monocarbocyclic arylsulfonyloxy, e.g. phenylsulfonyloxy. R is a hydrocarbon residue which is either aliphatic, aromatic or cycloaliphatic.

The reaction is preferably effected in a solvent, such as dimethylformamide, CHCI or acetonitrile, in which case the substituent Y, e.g. a halogen, appears in the obtained final product as anion X The solvents are not limited to these, however, and other solvents, such as dichloromethane, dioxane, tetrahydrofurane or nitrobenzene, can be used alternatively.

The reaction is conducted within a temperature range between -10 C. and 200 0., preferably between +20 C. and C. Normally, the reaction products of Formula I separate from the reaction mixture and are purified by recrystallization from, for example, lower alkanols, such as ethanol or isopropanol.

Furthermore, a compound of Formula V:

wherein each of R and R is CHO; or R is CH=NOH and R is CHO; or R1 IS and R2 IS R,

alkali, such as NaOH or KOH, preferably in an aqueous employed; for topical application salves or creams which or aqueous-ethanolic solution at temperatures between can be sterilized or mixed with auxiliary substances, such 20 C. and +l C., as described in greater detail in as preservatives, stabilizers or wetting agents, or salts for Houben-Weyl, Methoden der Organischen Chemie, vol. influencing the osmotic pressure, or with buffer substances, VH/l (1954), pp. 471-474. However, it is likewise posare preferred. sible to employ solvent mixtures of water with dimethyl Each of the pharmaceutically active compounds of this formamide, dioxane, dimethyl sulfoxide, acetonitrile or invention may incorporated, for Oral administratetrahydrofurane. Working-up is advantageously effected tion, in a tablet as the sole active ingredient. A typical by concentrating the reaction mixture gently by evaporadosage tablet is constituted by from 1 to 3 percent binder, tion under vacuum and isolating the reaction product of e.g. tragacanth; from 3 to 10 percent disintegrating agent, Formula I by extraction with isopropanol, e.g. corn, starch; from 2 to 10 percent lubricant, e.g. tal- F th th anion X9 i a compound f F l I cum; from 0.25 to 1.0 percent lubricant, e.g. magnesium can be replaced by noth anion e, Th th io stearate; an average dosage of active ingredient; and q.s. X can represent a chlorine ion or hydroxyl ion and can 100 percent of filler, -elactose; all Percentages being y subsequently be exchanged, in accordance with conven- Weight Tablets are P p according to Standard tablettional methods, for another anion, e.g. converted by treatg t n q Which am Well known in the 6111- ment with perchloric acid into the corresponding bis-perploying the necessary amounts of conventional granulatchlorate or by the eifect of sodium methane sulfonate into g liq i e.gaICO I SD30 and purified water. An exthe corresponding bis-methanesulfonate. emplary tabletting formulation for the instant active com- For pharmaceutically acceptable quaternary salts of pounds is: Formula I the anion X may be that of an organic acid, Parts e.g. tartaric acid; inorganic acid, e.g. hydrochloric acid, Compound of Example 1 50 hydrobromic acid and sulfuric acid; monobasic acid, e.g. ragacanth 2 an alkanesulfonic acid, such as methanesulfonic acid; di- Lactose 39.5 basic acid, e.g. succinic acid; tribasic acid, e.g. phosphoric Corn starch 5 acid and citric acid; saturated acid, e.g. acetic acid; eth- Talcum 3 ylenically unsaturated acid, e.g. maleic acid and fumaric Magnesium stearate 0.5 acid; or that of an aromatic acid, e.g. salicylic acid and Alcohol SD-30, q.s. an arylsulfonic acid, such as benzenesulfonic acid. The Purified water, q.s.

selected anion X does not nullify the therapeutic proper- 3O ties of compounds I; selection is made, rather, on thera- AS can be Seen from Table Y Y peutic acceptability. The novel compounds of general For- Y )-Py YU-[( 3 y )-py mula I are normally crystalline, water-soluble salts. Y dichloride eXhibitS a far Intermediates of Formula II or III are obtained by regreater pfoleclive efleift than the cPmmefcial p f pf acting pyridine-Z-aldoxime or compounds of Formula IV tlofl (acme agent! X X- II with disubstituted ethers of Formula VI g y -pi' g 5 3 y l d c e f emale mice 0 e ine, w ic mice were oral y Y CH2O CHFY (VI) poisoned under atropine protection with commercial inwherein Yhas the above-indicated meaning, secticidal preparations of the alkyl phosphate group.

TABLE 1 Toxicity Tests on Female Mice of the NMRI-Line Regarding the Influence of Toxogonin and 118-6 on the Toxicity of Insecticidal Preparations CD intravenously 1 LDw p. 05 in Preparation L/kg. Toxogonin HS-G PD5 (50% Phosdrin) 15 (13.5-17.5) 19.4 (15.8-25.6) 3.3 (2.3-4.5) Meta-Systox (50% Demetou-O-methyl sulfoxide) 86 (75-101) 29.0 (21.0-40.0) 2.0 (1.5-3.0) Malathion (technical) (1% solution in dimethyl sulioxide) z 145 0- 10-50 in each 0659, dead 4 4 Anthio (25% Formothion) 5 1,100 ($504,400) No survival (tested up to 50 mgJkg.) h... 3 15.0 (1.0-25.0)

1 As compared to double the oral LDro of the insecticidal preparation in mgJkg. i Contrary to t e other preparations tested, this dosage refers to the active agent.

I 1 hours.

preferably in inert solvents, such as chloroform, dichlo- Thus, HS-6 is six times as effective as Toxogonin romethane, acetonitn'le, nitromethane, dimethylsulfoxide, against PD poisoning (active agent: 0,0dimethyl-cardimethylformamide, dioxane or tetrahydrofuran. Preferbomethoxy-propenyl phosphate); about 15 times as efiecably, the reaction components are employed in a molar tive as Toxogonin against Meta-Systox poisoning (active ratio of 111.2, and the process is conducted at temperaagent: dimethyl-thionophosphoric acid-(B-ethylmercaptures of up to 80 C. In general, the reaction products to)-ethyl ester); and is significantly stronger, in particuare obtained in crystalline phase and obtained in a sufiilar, against Malathion poisoning (active agent: 0,0-diciently pure form for further reactions by post-washing methyl-dithiophosphoric acid-S-(1,2-dicarbethoxy-ethyl)- with an inert solvent. ester) and against Anthio poisoning (active agent: 0,0- The novel compounds of Formula I can be processed dimethyl-dithio-phosphorylacetic acid N methyl N- to all forms of preparations customary for pharmaceutical formylamide) p p P r P t drages, Solutions, The experiments listed in Table l were conducted in emulsions, Y P and injection Solutions can be Produced the same manner as those published by Zech, Erdmann therefrom. Suitable pharmaceutical excipients are those d Engelhard i Arzneimittelforschung, 17, 1200,

organic substances which are adapted for parenteral, en- T bl 4 teral or topical application and which do not react with Th t t i l employed r f l i f th the novel compounds, such as water, vegetable Oils, r y- NMRI-line. Following the practice with respect to poisons,

thyl n g y s, g lactose, almylose, magnesium the animals were poisoned orally with the insecticidal Sleafflte, talc, Vaseline, cholesterol Especially Suitaalkyl phosphates listed in Table l. The counter-treatment ble for parenteral application are solutions, preferably ith 113.5 or T i was fl t d 15 minutes after oily or aqueous solutions, as well as suspensions or emulthe oral feeding of the alkyl phosphate by a single intrasions. For enteral application tablets or drages can be venous administration of the antidote (without atropine);

however, the administered dose of the antidote was varied in order to determine quantitative relationships (determination of CD [=median curvative dosage; a dose that abolishes symptoms in 50 percent of the test subjects]).

Th superiority of HS-6 as an antidote becomes even more apparent when considering that, in accordance with German Pat. 1,190,941 and US. Pat. 3,137,702, substantial advantages are claimed for Toxogonin over 2-PAM (2 hydroxy iminomethyl-N-methyl-pyridinium iodide) and TMB-4 (1,3 bis-[4'-hydroxy-iminomethyl-pyridinium-(1')]-propane dibromide) against poisoning by phosphorus-containing plant-protective agents. For example, the superiority of HS-6 and [(2-hydroxy-iminomethyl)- pyridinium 1) methyl] [(4-hydroxy-iminomethyl)- pyridinium-(1)-methyl]-ether dichloride can be explained by the fact that these compounds represent a novel antidote principle: they eifect a hydrolytic inactivation of poisonous phosphoric acid esters within the organism. In this connection, they are less poisonous than the antidote TMB-4. HS-6 is only half as toxic as Toxogonin, as can be seen from Table 2.

1 2-hydroxy-irninomethyl-N-methyl-pyridinium chloride. 1 Z-hydroxy-iminomethyl-Nmethyl-pyridinium methyl sulfate.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 In 150 ml. of dry chloroform 1.22 g. of pyridine-Z-aldoxime is dissolved in the warm state and mixed with 2.4 g. of [(2-hydroxy-iminomethyl)-pyridinium-( 1)-methyl]- chloromethyl-ether chloride. Under vigorous stirring and exclusion of moisture, the suspension is maintained at the boiling point for hours. Thereafter, the suspension is vacuum filtered while still warm, and washed twice, once with dry alcohol and once with diethylether.

The reaction product is 2.6 g. of crude bis-[ (2-hydroxyiminomethyl)-pyridinium( 1) methyl] ether dichloride, exhibiting, after recrystallization from aqueous methanol, a decomposition point starting at 175 C.

Replacing the pyridine-Z-aldoxime with an equivalent of either Z-methylpyridine or picolinic acid methyl ester results in the preparation, in similar manner, of the corresponding compound I.

EXAMPLE 2 In 32.5 ml. of absolute acetonitrile 1.22 g. of pyridine- 3-aldoxime is dissolved and reacted, analogously to Example 1, with 2.4 g. of [(Z-hydroxy-iminomethyl)-pyri-- dinium-( 1 )methyl] -chloromethyl-ether chloride.

2.9 g. of crude [(2-hydroxy-iminomethyl)-pyridinium- (1)-methyl]-[(3-hydroxy-iminomethyl)-pyridinium (1)- methyl]-ether dichloride are obtained, exhibiting a decomposition point of 169-l70 C. after recrystallization from methanol/isopropanol.

Replacing the pyridine-3-aldoxime with an equivalent of either 3-methylpyridine or nicotinic acid methyl ester results in the preparation, in similar manner, of the corresponding compound I.

6 EXAMPLE 3 In 15 ml. of absolute chloroform, 1.22 g. of pyridine-4- aldoxime are dissolved in the warm phase and reacted, analogously to Example 1, with 2.4 g. of [(2-hydroxyiminomethyl) pyridinium l) methyl] chloromethylether chloride.

2.6 g. of crude [(Z-hydroxy-iminomethyl)-pyridinium- (1)-methyl]-[(4-hydroxy-iminomethyl)-pyridinium (1) methyl]-ether dichloride is obtained, having a decomposition point of 177 -178 C. after recrystallization from methanol/isopropanol, with the addition of a small amount of acetone.

Replacing the pyridine-4-aldoxime with an equivalent of either 4-methylpyridine or isonicotinic acid methyl ester results in the preparation, in similar manner, of the corresponding compound I.

EXAMPLE 4 1.22 g. of nicotinic acid amide and 2.4 g. of [(2-hydroxy iminomethyl) pyridinium (1) methyl] chloromethyl-ether chloride are heated in 60 ml. of dimethyl formamide for 4 hours at 3040 C. and then worked up analogously to Example 1, thus yielding 2.7 g. of crude [(2 hydroxy iminomethyl) pyridinium (1) methyl]- [(3-carbamoyl) -pyridinium-( 1 )-methyl] -ether dichloride, which melts, after recrystallization from aqueous isopropanol, at 155156 C.

Replacing the nicotinic acid amide with an equivalent of either picolinic acid amide or isonicotinic acid amide results in the preparation, in similar manner, of the corresponding compound I.

EXAMPLE 5 A mixture of 7.9 g. of absolute pyridine and 1.2 g. of [(2 hydroxy iminomethyl) pyridinium (1) methyl]- chloromethyl-ether chloride in 30 ml. of dimethyl formamide is heated, under stirring, for 5 hours at 50 C. Then, the precipitate is vacuum filtered and Washed with chloroform and diethylether. After recrystallization from aqueous methanol/isopropanol, there is obtained 1.3 g. of [(2- hydroxy iminomethyl) pyridinium (1) methyl]- [pyridinium-(1)-methyl]-ether dichloride, having a decomposition point of 142-143 C.

EXAMPLE 6 3.65 g. of bis-[2-formyl-pyridinium-(1)-rnethyl]-ether dichloride are dissolved in 40 ml. of water and heated for 15 minutes on a water bath with 1.68 g. of hydroxylamine hydrochloride. Then, the hydrochloric solution is neutralized with sodium acetate, once again heated for 10 minutes, and 0.204 g. of sodium nitrate is added thereto. Upon cooling, the nitrate of bis-[Z-hydroxy-iminomethylpyridinium-(l)-methyl]-ether crystallizes in a 65% yield.

The starting material is obtained as follows:

Under stirring, at 60-80 C., 1.48 g. of dichloromethyl ether is added dropwise to 2.4 g. of pyridine-Z-aldehyde (freshly distilled) in 4 ml. of dry dimethyl formamide. After a short time, the dichloride precipitates, is vacuum filtered, and washed With diethylether. Yield: at least The yellowish, slightly oily bis-[2-formyl-pyridinium-(1)-methyl]-ether dichloride is precipitated as a colorless, crystalline dihydrate from a very small amount of water to which some HCl is added, with acetone.

EXAMPLE 7 Under cooling, 1.8 g. of dipotassium hydrogen phosphate in 20 ml. of water are added under stirring to 3.6 g. of bis-[2-hydroxy-iminomethyl pyridinium-(1)-methyl]-ether dichloride in 16 ml. of water. Bis-[Z-hydroxyiminomethyl-pyridinium (1) methyl]-ether monophosphate precipitates at once in shiny, bright yellow platelets.

EXAMPLE 8 3.6 g. (0.01 mol) of bis-[Z-hydroxy-iminomethyl-pyridinium-(1)-methyl]-ether dichloride in 20 ml. of water are combined under stirring with 1.7 g. of sodium bicarbonate in 20 ml. of water. There precipitates immediately bis-[2 hydroxy-iminomethyl-pyridinium 1) methyl]- ether dihydrogen carbonate in the form of a yellowish salt.

EXAMPLE 9 3.59 g. of bis-[2-hydroxy-iminomethyl-pyridinium-(1)- methylJ-ether dichloride are dissolved in 70 ml. of warm 90% aqueous methanol and mixed, under stirring, with 3.30 g .of silver succinate. The reaction solution is heated at 50-60 C. for 5 minutes. The thus-precipitating product is filtered ofi. After the addition of diethylether, bis- [2-hydroxy-iminomethyl-pyridinium (1) methylJ-ether succinate crystallizes.

EXAMPLE Under heating, 3.05 g. of pyridine-Z-aldoxime are dissolved in ml. of dry chloroform. With stirring and under exclusion of moisture, 3.16 g. of u,u-dichlorodimethyl ether in 5 ml. of dry chloroform are slowly added dropwise at 40-50 C. (about 30 drops per minute). After 10 minutes, the solution becomes cloudy. The agitation is continued for 4 hours at 45 C., and the reaction mixture is allowed to stand overnight.

The precipitate is vacuum filtered, washed with chloroform and dried under vacuum at 60 0., thus yielding 4.78 g. of [(Z-hydroxy iminomethyl) pyridinium-(1)- methyl] -chloromethyl-ether chloride having a decomposition starting point of 122 C., melting at 138 C.

This crude product is sufficiently clean for further reactions.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of the following claims.

What is claimed is: 1. A pharmaceutically acceptable quaternary salt of the formula wherein R is COO-CH in one of the positions 2-, 3- and 4- and X is an equivalent of a monoor polyvalent anion.

2. A pharmaceutically acceptable quaternary salt of the formula References Cited UNITED STATES PATENTS 3,045,025 7/1962 Hackley et a1 260296 3,137,702 6/1964 Liittringhaus et a1. 260296 FOREIGN PATENTS 1,190,941 4/ 1965 Germany 260296 HENRY R. JILES, Primary Examiner G. TODD, Assistant Examiner US. Cl. X.R.

260294.8 R, 295 R, 295 Q, 295.5 R, 296 D, 296 M; 424263, 266 

